Impairment of an endothelial NAD(+)-H2S signaling network is a reversible cause of vascular aging
Open accessAbstract
A decline in capillary density and blood flow with age is a major cause of mortality and morbidity. Understanding why this occurs is key to future gains in human health. NAD precursors reverse aspects of aging, in part, by activating sirtuin deacylases (SIRT1-SIRT7) that mediate the benefits of exercise and dietary restriction (DR). We show that SIRT1 in endothelial cells is a key mediator of pro-angiogenic signals secreted from myocytes. Treatment of mice with the NAD+ booster nicotinamide mononucleotide (NMN) improves blood flow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect augmented by exercise or increasing the levels of hydrogen sulfide (H 2 S), a DR mimetic and regulator of endothelial NAD+ levels. These findings have implications for improving blood flow to organs and tissues, increasing human performance, and reestablishing a virtuous cycle of mobility in the elderly.
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NADP boosters can be used to resolve the NAD depletion issue and are able to prevent senescence in ECs and VSMCs.
“NADP boosters (nicotinamide mononucleotide,158 nicotinamide riboside,159 P7C3,160 apigenin161) can be used resolve the NAD depletion issue and are able to prevent senescence in ECs158 and VSMCs.159”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [158]
NMN supplementation increased endothelial cell number and improved endothelial cell function by increasing blood flow and endurance in elderly mice via a SIRT1-dependent mechanism.
“NMN supplementation also increased the number of endothelial cells and improved endothelial cell function by increasing blood flow and endurance in elderly mice by a SIRT1-dependent mechanism210.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [210]
Premature endothelium senescence reversibly triggers vascular ageing and the age-associated decrease in exercise endurance in old mice.
“It was reported that premature endothelium senescence reversibly triggers vascular ageing and the age-associated decrease in exercise endurance in old mice [42].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [42]
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“In young muscle, SIRT1 is required for ischemia-induced neovascularization (Potente et al., 2007), vascular relaxation 74 Cell 173, 74–89, March 22, 2018 ª 2018 Elsevier Inc. (Mattagajasingh et al., 2007; Pearson et al., 2008; Ungvari et al., 2010), and is implicated in EC senescence (Ota et al.,…”
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“REAGENT or RESOURCE SOURCE IDENTIFIER Methocel (viscosity: 4000 cps) Sigma-Aldrich Cat#M0512 BS1 lectin-FITC Sigma-Aldrich Cat#9381 Fetal Bovine Serum (FBS) Life Technologies Cat#10099141 Penicillin/Streptomycin (10,000 U/mL) Life Technologies Cat#15140122 Cytochrome c Oxidase from bovine heart Sigma-Aldrich Cat#C-549…”
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Self-citationAmino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production
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“It increases SIRT1 activity, protects against oxidative stress, and can promote angiogenesis (Longchamp et al., 2018).”
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“A more recent approach has been to restore NAD levels by treating with NAD precursors such as nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN) (Cantó et al., 2015; Gomes et al., 2013; Mouchiroud et al., 2013; Ramsey et al., 2008).”
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“…is required for ischemia-induced neovascularization (Potente et al., 2007), vascular relaxation 74 Cell 173, 74–89, March 22, 2018 ª 2018 Elsevier Inc. (Mattagajasingh et al., 2007; Pearson et al., 2008; Ungvari et al., 2010), and is implicated in EC senescence (Ota et al., 2007; Zu et al., 2010).”
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“…The Jackson Laboratory JAX:007676 Mouse: C57BL/6J Myog-Cre Gift from Dr. Eric N. Olson, UT Southwestern TX Li et al., 2005 Mouse: C57BL/6J MCK-PGC-1a Gift from Dr. Bruce Spiegelman, Dana Farber Cancer Center MA Lin et al., 2002 Oligonucleotides Sir2A6860…”
PARP-2 Regulates SIRT1 Expression and Whole-Body Energy Expenditure
Bai, P., Cantó, C., Brunyánszki, A., Huber, A., Szántó, M., Cen, Y., Yamamoto, H., Houten, S. M., Kiss, B., Oudart, H., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.03.013 · Cited by 250 · cited 2× · see citing works
“During aging, the level of NAD+ declines in many tissues, in part, due to increased activity of the NAD-consuming enzymes CD38 and PARP1 (Bai et al., 2011b; Camacho-Pereira et al., 2016; Li et al., 2017; Mouchiroud et al., 2013).”
Control of cardiac myosin heavy chain gene expression
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Hydrogen sulfide increases thermotolerance and lifespan in Caenorhabditis elegans
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“SIRT1 and H2S protect against oxidative stress-mediated apoptosis and senescence (Miller and Roth, 2007; Salminen et al., 2013; Suo et al., 2013; Wu et al., 2015).”
Groen, B. B. L., Hamer, H. M., Snijders, T., van Kranenburg, J. M. X., Frijns, D., Vink, H., & van Loon, L. J. C. (2014) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00919.2013 · Cited by 224 · cited 2× · see citing works
“For reasons that are unclear, as we age there is an increase in muscle EC apoptosis, decreased neovascularization, and blood vessel loss (Groen et al., 2014; Wang et al., 2014), resulting in reduced muscle mass (sarcopenia) and a decline in strength and endurance in the later decades of life, even with exercise (Denis…”
Small-Molecule Allosteric Activators of Sirtuins
Sinclair, D. A., & Guarente, L. (2011) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010611-134657 · Cited by 223 · cited 1× · see citing works
“SIRT1-activating compounds (STACs) such as resveratrol and SRT1720 have been pursued as a strategy for ameliorating agerelated diseases (Hubbard et al., 2013; Sinclair and Guarente, 2014).”
Self-citationNoseda, M., Chang, L., McLean, G. W., Grim, J. E., Clurman, B. E., Smith, L. L., & Karsan, A. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.20.8813-8822.2004 · Cited by 218 · cited 1× · see citing works
“NMN treatment induced proliferation (Figure S5L) and reduced apoptosis in ECs in a SIRT1-dependent manner, consistent with an inhibition of Notch (Noseda et al., 2004) (Figure S5M).”
NAD <sup>+</sup> metabolism: A therapeutic target for age-related metabolic disease
Mouchiroud, L., Houtkooper, R. H., & Auwerx, J. (2013) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2013.789479 · Cited by 193 · cited 2× · see citing works
“During aging, the level of NAD+ declines in many tissues, in part, due to increased activity of the NAD-consuming enzymes CD38 and PARP1 (Bai et al., 2011b; Camacho-Pereira et al., 2016; Li et al., 2017; Mouchiroud et al., 2013).”
Isolation of endothelial cells from fresh tissues
B, J. R. V. B., Rousch, M., Castermans, K., van der Linden, E. P. M., & Griffioen, A. W. (2008) · Nature Protocols · doi:10.1038/nprot.2008.71 · Cited by 188 · see citing works
A conserved NAD + binding pocket that regulates protein-protein interactions during aging
Li, J., Bonkowski, M. S., Moniot, S., Zhang, D., Hubbard, B. P., Ling, A. J. Y., Rajman, L. A., Qin, B., Lou, Z., Gorbunova, V. A., et al. (2017) · Science · doi:10.1126/science.aad8242 · Cited by 188 · cited 4× · see citing works
“, 2012), and protect against age-related physiological decline including reduced DNA repair, mitochondrial dysfunction, and glucose intolerance (de Picciotto et al., 2016; Gomes et al., 2013; Li et al., 2017; Yoshino et al., 2011).”
InfluentialSelf-citationSIRT6 protects human endothelial cells from DNA damage, telomere dysfunction, and senescence
Figueras, A. C., Uryga, A., Walters, G., & Erusalimsky, J. D. (2012) · Cardiovascular Research · doi:10.1093/cvr/cvs352 · Cited by 182 · cited 1× · see citing works
“SIRT3 and SIRT6 also increase the angiogenic potential of ECs in culture (Cardus et al., 2013; Wei et al., 2017).”
Muscle‐specific VEGF deficiency greatly reduces exercise endurance in mice
Olfert, I. M., Howlett, R. A., Tang, K., Dalton, N. D., Gu, Y., Peterson, K. L., Wagner, P. D., & Breen, E. C. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2008.164384 · Cited by 166 · cited 2× · see citing works
“The performance of organs and tissues is critically dependent on a functional microcapillary network that maintains a supply of oxygen, exchanges heat and nutrients, and removes waste products (Olfert et al., 2009).”
Lower skeletal muscle capillarization and VEGF expression in aged vs. young men
Ryan, N. A., Zwetsloot, K. A., Westerkamp, L. M., Hickner, R. C., Pofahl, W. E., & Gavin, T. P. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00827.2005 · Cited by 165 · cited 2× · see citing works
“, 2014), resulting in reduced muscle mass (sarcopenia) and a decline in strength and endurance in the later decades of life, even with exercise (Denis et al., 1986; Prior et al., 2016; Ryan et al., 2006).”
Turner, N. A., Hariharan, K., Tid-Ang, J. D., Frangioudakis, G., Beale, S. M., Wright, L. E., Zeng, X., Leslie, S. J., Li, J.-Y., Kraegen, E. W., et al. (2009) · Diabetes · doi:10.2337/db09-0784 · Cited by 162 · cited 1× · see citing works
“Supernatants were used to determine the activity for citrate synthase (CS) and succinate dehydrogenase (SDH) as described previously (Turner et al., 2009).”
Self-citationAxitinib for the Management of Metastatic Renal Cell Carcinoma
Escudier, B. J., & Gore, M. E. (2011) · Drugs in R&D · doi:10.2165/11591240-000000000-00000 · Cited by 148 · see citing works
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“, 2014), resulting in reduced muscle mass (sarcopenia) and a decline in strength and endurance in the later decades of life, even with exercise (Denis et al., 1986; Prior et al., 2016; Ryan et al., 2006).”
Sirtuin 3 Deficiency Accelerates Hypertensive Cardiac Remodeling by Impairing Angiogenesis
Wei, T., Huang, G., Gao, J., Huang, C., Sun, M., Wu, J., Bu, J., & Shen, W. (2017) · Journal of the American Heart Association · doi:10.1161/jaha.117.006114 · Cited by 137 · cited 1× · see citing works
“SIRT3 and SIRT6 also increase the angiogenic potential of ECs in culture (Cardus et al., 2013; Wei et al., 2017).”
Self-citationBorradaile, N. M., & Pickering, J. G. (2009) · Aging Cell · doi:10.1111/j.1474-9726.2009.00453.x · Cited by 129 · cited 3× · see citing works
“NAD precursors increase the angiogenic capacity of ECs in cell culture (Borradaile and Pickering, 2009; HughesLarge et al., 2014), improve the exercise capacity of young mice (Cantó et al.”
InfluentialGYY4137, a Novel Water-Soluble, H2S-Releasing Molecule
Rose, P. E., Dymock, B. W., & Moore, P. K. (2015) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2014.11.014 · Cited by 118 · cited 2× · see citing works
“In all cases, otherwise indicated, animals were administered NMN (400 mg/kg/day), NaHS (20 mg/kg/day) and/or GYY4137 (20mg/kg/day) (Rose et al., 2015) via drinking water at pH 7.2.”
InfluentialApoptosis in capillary endothelial cells in ageing skeletal muscle
Wang, H., Listrat, A., Meunier, B., Gueugneau, M., Coudy‐Gandilhon, C., Combaret, L., Taillandier, D., Polge, C., Attaix, D., Lethias, C., et al. (2014) · Aging Cell · doi:10.1111/acel.12169 · Cited by 109 · cited 2× · see citing works
“For reasons that are unclear, as we age there is an increase in muscle EC apoptosis, decreased neovascularization, and blood vessel loss (Groen et al., 2014; Wang et al., 2014), resulting in reduced muscle mass (sarcopenia) and a decline in strength and endurance in the later decades of life, even with exercise (Denis…”
Uddin, G. M., Youngson, N. A., Sinclair, D. A., & Morris, M. J. (2016) · Frontiers in Pharmacology · doi:10.3389/fphar.2016.00258 · Cited by 95 · cited 1× · see citing works
“Alternatively, NAD levels in muscle and liver weremeasured by assay in-house developedmethod (Uddin et al., 2016).”
Self-citationWu, D., Hu, Q., Liu, X., Pan, L., Xiong, Q., & Zhu, Y. Z. (2014) · Nitric Oxide · doi:10.1016/j.niox.2014.11.006 · Cited by 92 · cited 3× · see citing works
“In mammals, ectopic treatment with H2S induces SIRT1 in response to oxidative stress (Suo et al., 2013; Wu et al., 2015; Zheng et al., 2014) and protects rat hearts from ischemia/reperfusion via a mechanism requiring SIRT1 (Hu et al., 2016).”
Hine, C., & Mitchell, J. R. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.12.010 · Cited by 92 · cited 2× · see citing works
“Cell 173, 74–89, March 22, 2018 75 (legend on next page) 76 Cell 173, 74–89, March 22, 2018 Another DRmimetic is hydrogen sulfide (H2S), a gas generated endogenously by cystathionine b-synthase (CBS) and/or cystathionine g-lyase (CSE) (Hine and Mitchell, 2015).”
Self-citationSuo, R., Zhan-zhi, Z., Tang, Z., Ren, Z., Liu, X., Liu, L.-S., Wang, Z., Tang, C., Wei, D., & Zhi-sheng, J. (2013) · Molecular Medicine Reports · doi:10.3892/mmr.2013.1417 · Cited by 89 · cited 3× · see citing works
“In mammals, ectopic treatment with H2S induces SIRT1 in response to oxidative stress (Suo et al., 2013; Wu et al., 2015; Zheng et al., 2014) and protects rat hearts from ischemia/reperfusion via a mechanism requiring SIRT1 (Hu et al., 2016).”
Frederick, D. W., Davis, J. G., Dávila, A., Agarwal, B., Michán, S., Puchowicz, M. A., Nakamaru‐Ogiso, E., & Baur, J. A. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.579565 · Cited by 88 · cited 2× · see citing works
“NMN did not alter the capillarity or exercise capacity of sedentary animals younger than 12 months (not shown), consistent with overexpression of Nampt, an NAD biosynthetic gene (Frederick et al., 2015).”
Ross, J. M. (2011) · Journal of Visualized Experiments · doi:10.3791/3266 · Cited by 81 · cited 1× · see citing works
“Cytochrome c oxidase staining of muscle sections was performed according to the published protocol (Ross, 2011).”
Morscher, S., Driessen, W., Claussen, J., & Burton, N. (2014) · Photoacoustics · doi:10.1016/j.pacs.2014.06.001 · Cited by 78 · cited 1× · see citing works
“The animals were then placed horizontally in the imaging chamber of MSOT inVision 256-TF small animal imaging system and three-dimensional scanning of the lower portion was performed as per manufacture’s protocol (Morscher et al., 2014).”
Transthoracic Echocardiography in Mice
Respress, J. L., & Wehrens, X. H. T. (2010) · Journal of Visualized Experiments · doi:10.3791/1738 · Cited by 78 · see citing works
Oommen, S., Gupta, S. K., & Vlahakis, N. E. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.175158 · Cited by 76 · see citing works
Age-Related Changes in the Microcirculation of Skeletal Muscle
Degens, H. (1998) · Advances in experimental medicine and biology · doi:10.1007/978-1-4615-4863-8_40 · Cited by 68 · cited 1× · see citing works
“From the age of 40 onward, tissue perfusion declines steadily and seemingly inexorably, leading to organ dysfunction and increasing frailty in the last decades of life (Degens, 1998; Le Couteur and Lakatta, 2010).”
Denis, C., Chatard, J., Dormois, D., Linossier, M., GEYSSANT, A., & Lacour, J. R. (1986) · PubMed · Cited by 68 · see citing works
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“Despite the importance of capillary loss to human health, it is surprising how little we understand about its underlying causes (Le Couteur and Lakatta, 2010).”
Aspartoacylase-LacZ Knockin Mice: An Engineered Model of Canavan Disease
Mersmann, N., Tkachev, D., Jelinek, R., Röth, P. T., Möbius, W., Ruhwedel, T., Rühle, S., Weber‐Fahr, W., Sartorius, A., & Klugmann, M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020336 · Cited by 48 · cited 1× · see citing works
“Rotarod test Motor coordination was assessed using the rotarod test as previously described (Mersmann et al., 2011).”
Hu, M.-Z., Zhou, B., Mao, H.-Y., Sheng, Q., Du, B., Chen, J., Pang, Q., & Ji, Y. H. (2016) · International Heart Journal · doi:10.1536/ihj.15-506 · Cited by 48 · cited 1× · see citing works
“In mammals, ectopic treatment with H2S induces SIRT1 in response to oxidative stress (Suo et al., 2013; Wu et al., 2015; Zheng et al., 2014) and protects rat hearts from ischemia/reperfusion via a mechanism requiring SIRT1 (Hu et al., 2016).”
Zhang, Y., Jiang, G., Sauler, M., & Lee, P. J. (2013) · The FASEB Journal · doi:10.1096/fj.13-231225 · Cited by 46 · cited 5× · see citing works
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InfluentialBaltgalvis, K. A., White, K., Li, W., Claypool, M. D., Lang, W., Alcantara, R. R., Singh, B., Friera, A. M., McLaughlin, J. R., Hansen, D., et al. (2014) · American Journal of Physiology. Heart and Circulatory Physiology · doi:10.1152/ajpheart.00839.2013 · Cited by 41 · cited 1× · see citing works
“The difference in maximum and minimum video intensity was determined as the peak enhancement (Baltgalvis et al., 2014).”
Zheng, M., Qiao, W., Cui, J., Liu, L., Liu, H., Wang, Z., & Yan, C. (2014) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-014-2046-y · Cited by 40 · cited 2× · see citing works
“In mammals, ectopic treatment with H2S induces SIRT1 in response to oxidative stress (Suo et al., 2013; Wu et al., 2015; Zheng et al., 2014) and protects rat hearts from ischemia/reperfusion via a mechanism requiring SIRT1 (Hu et al., 2016).”
Transthoracic Echocardiography in Mice
Respress, J. L., & Wehrens, X. H. T. (2010) · Journal of Visualized Experiments · doi:10.3791/1738-v · Cited by 37 · see citing works
Hughes-Large, J. M., Pang, D., Robson, D. L., Chan, P., Toma, J., & Borradaile, N. M. (2014) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2014.10.090 · Cited by 35 · see citing works
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“A potential candidate is CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2), an inhibitor of hypoxia-inducible factor 1 (HIF-1a) signaling that is implicated in type 2 diabetes (Wang et al., 2016).”
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Sarcopenia: Aging-Related Loss of Muscle Mass and Function
Larsson, L., Degens, H., Li, M., Salviati, L., Lee, Y. I., Thompson, W., Kirkland, J. L., & Sandri, M. (2019) · Physiological Reviews · doi:10.1152/physrev.00061.2017 · Cited by 1,797 · see citing works
NAD+ metabolism and its roles in cellular processes during ageing
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Modulation of cellular processes by histone and non-histone protein acetylation
Shvedunova, M., & Akhtar, A. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00441-y · Cited by 975 · see citing works
NAD+ in Brain Aging and Neurodegenerative Disorders
Lautrup, S., Sinclair, D. A., Mattson, M. P., & Fang, E. F. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.09.001 · Cited by 790 · see citing works
“Mounting evidence supports a critical role for NAD+ in stem cell rejuvenation, including in HSCs, endothelial stem cells, muscle stem cells, and melanocyte stem cells (Das et al., 2018; Vannini et al., 2019; Zhang et al., 2016).”
Self-citationMolecular mechanisms of dietary restriction promoting health and longevity
Green, C. L., Lamming, D. W., & Fontana, L. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00411-4 · Cited by 714 · see citing works
Mechanisms of Dysfunction in the Aging Vasculature and Role in Age-Related Disease
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Loss of epigenetic information as a cause of mammalian aging
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Self-citationNAD+ homeostasis in health and disease
Katsyuba, E., Romani, M., Hofer, D., & Auwerx, J. (2020) · Nature Metabolism · doi:10.1038/s42255-019-0161-5 · Cited by 627 · see citing works
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Physiological roles of hydrogen sulfide in mammalian cells, tissues, and organs
Cirino, G., Szabó, C., & Papapetropoulos, A. (2022) · Physiological Reviews · doi:10.1152/physrev.00028.2021 · Cited by 568 · see citing works
Reversal of epigenetic aging and immunosenescent trends in humans.
Fahy, G. M., Brooke, R. T., Watson, J. P., Good, Z., Vasanawala, S. S., Maecker, H., Leipold, M. D., Lin, D. T. S., Kobor, M. S., & Horvath, S. (2019) · Aging Cell · doi:10.1111/acel.13028 · Cited by 477 · see citing works
“Given the relationship between age‐related tissue NAD+ depletion and the onset of aging phenotypes (Das et al., 2018; Poljsak & Milisav, 2016), an increased tissue NAD+ content could be connected to our observations of reversed epigenetic aging, to the general association of higher LMRs with better…”
BackgroundLópez-Otín, C., & Kroemer, G. (2021) · Cell · doi:10.1016/j.cell.2020.11.034 · Cited by 499 · see citing works
Sirtuins and NAD + in the Development and Treatment of Metabolic and Cardiovascular Diseases
Kane, A. E., & Sinclair, D. A. (2018) · Circulation Research · doi:10.1161/circresaha.118.312498 · Cited by 490 · see citing works
Self-citationDefined p16High Senescent Cell Types Are Indispensable for Mouse Healthspan
Grosse, L., Wagner, N., Emelyanov, A., Molina, C., Lacas-Gervais, S., Wagner, K.-D., & Bulavin, D. V. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.05.002 · Cited by 460 · see citing works
Elhassan, Y. S., Kluckova, K., Fletcher, R. S., Schmidt, M. S., Garten, A., Doig, C. L., Cartwright, D. M., Oakey, L., Burley, C. V., Jenkinson, N., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.043 · Cited by 448 · see citing works
Cai, Y., Song, W., Li, J., Jing, Y., Liang, C., Zhang, L., Zhang, X., Zhang, W., Liu, B., An, Y., et al. (2022) · Science China Life Sciences · doi:10.1007/s11427-022-2161-3 · Cited by 436 · see citing works
Zhu, X., Chen, Z., Shen, W., Huang, G., Sedivy, J. M., Wang, H., & Ju, Z. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00646-9 · Cited by 410 · see citing works
“Other interventions that promote cysteine metabolism and hydrogen sulfide production also exhibit therapeutic benefits and delay tissue ageing.(357,379) Mitochondria represent the central platform of cellular metabolism and contain their own genome.”
BackgroundSelf-citationRole of NAD+ in regulating cellular and metabolic signaling pathways
Amjad, S., Nisar, S., Bhat, A. A., Shah, A. R., Frenneaux, M. P., Fakhro, K. A., Haris, M., Reddy, R. D., Patay, Z. J., Baur, J. A., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101195 · Cited by 394 · see citing works
“Interestingly, a study showed that NADþ repletion restores microvasculature and capillaries’ number and density in old mice [67].”
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Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span
Grunewald, M., Kumar, S., Sharife, H., Volinsky, E., Gileles‐Hillel, A., Licht, T., Permyakova, A., Hinden, L., Azar, S., Friedmann, Y., et al. (2021) · Science · doi:10.1126/science.abc8479 · Cited by 370 · see citing works
“Previous studies have shown that age-dependent decline of hippocampal neurogenesis (15), liver regeneration (16), and skeletal muscle exercise capacity (8) can be alleviated by improved VEGF signaling.”
BackgroundA systems view of the vascular endothelium in health and disease
Augustin, H. G., & Koh, G. Y. (2024) · Cell · doi:10.1016/j.cell.2024.07.012 · Cited by 370 · see citing works
Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production
Longchamp, A., Mirabella, T., Arduini, A., MacArthur, M. R., Das, A., Trevino-Villarreal, J. H., Hine, C., Ben‐Sahra, I., Knudsen, N. H., Brace, L. E., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.001 · Cited by 327 · see citing works
“In an accompanying manuscript, Das et al. (2018) report an interaction between H2S and SIRT1 in the regulation of angiogenesis as evidenced by the ability of H2S/NMN supplementation in old mice to reverse age-associated loss of muscle vascular density and improved exercise performance.”
BackgroundSelf-citationMiao, Y., Cui, Z., Gao, Q., Rui, R., & Xiong, B. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107987 · Cited by 312 · see citing works
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Self-citationEffects of hydrogen sulfide on mitochondrial function and cellular bioenergetics
Paul, B. D., Snyder, S. H., & Kashfi, K. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101772 · Cited by 283 · see citing works
Hallmarks of cardiovascular ageing
Abdellatif, M., Rainer, P. P., Sedej, S., & Kroemer, G. (2023) · Nature Reviews Cardiology · doi:10.1038/s41569-023-00881-3 · Cited by 284 · see citing works
Parkhitko, A. A., Jouandin, P., Mohr, S. E., & Perrimon, N. (2019) · Aging Cell · doi:10.1111/acel.13034 · Cited by 276 · see citing works
H2S-activatable near-infrared afterglow luminescent probes for sensitive molecular imaging in vivo
Wu, L., Ishigaki, Y., Hu, Y., Sugimoto, K., Zeng, W., Harimoto, T., Sun, Y., He, J., Suzuki, T., Jiang, X., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-14307-y · Cited by 252 · see citing works
Self-citationBacteria Boost Mammalian Host NAD Metabolism by Engaging the Deamidated Biosynthesis Pathway
Shats, I., Williams, J. G., Liu, J., Makarov, M. V., Wu, X., Lih, F. B., Deterding, L. J., Lim, C., Xu, X., Randall, T. A., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.02.001 · Cited by 242 · see citing works
Nicotinamide mononucleotide (NMN) as an anti-aging health product – Promises and safety concerns
Nadeeshani, H., Li, J., Ying, T., Zhang, B., & Lu, J. (2021) · Journal of Advanced Research · doi:10.1016/j.jare.2021.08.003 · Cited by 211 · see citing works
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Reynolds, J. C., Lai, R. W., Woodhead, J. S. T., Joly, J. H., Mitchell, C. J., Cameron-Smith, D., Lu, R., Cohen, P., Graham, N. A., Benayoun, B. A., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20790-0 · Cited by 199 · see citing works
Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases
Song, P., An, J., & Zou, M.-H. (2020) · Cells · doi:10.3390/cells9030671 · Cited by 198 · see citing works
Hydrogen sulfide (H2S) signaling in plant development and stress responses
Liu, H., Wang, J., Liu, J., Liu, T., & Xue, S. (2021) · aBIOTECH · doi:10.1007/s42994-021-00035-4 · Cited by 192 · see citing works
Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis
Stojanović, S. D., Fiedler, J., Bauersachs, J., Thum, T., & Sedding, D. G. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz919 · Cited by 188 · see citing works
Role of Hydrogen Sulfide in NRF2- and Sirtuin-Dependent Maintenance of Cellular Redox Balance
Corsello, T., Komaravelli, N., & Casola, A. (2018) · Antioxidants · doi:10.3390/antiox7100129 · Cited by 183 · see citing works
“Changes in SIRT1 activity in endothelial cells after exogenous administration of NaHS have been linked to regulation of intracellular levels of NAD+ [33].”
BackgroundHepatic stellate cell senescence in liver fibrosis: Characteristics, mechanisms and perspectives
Zhang, M., Salas, S. S., Damba, T., Borghesan, M., Demaria, M., & Moshage, H. J. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111572 · Cited by 180 · see citing works
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“Abhirup et al. reported that SIRT1 in ECs is necessary for the response to pro-angiogenic signals secreted from myocytes and treatment with NMN improved blood flow and endurance in elderly mice by increasing capillary density (Das et al., 2018).”
BackgroundYi, L., Maier, A. B., Tao, R., Lin, Z., Vaidya, A., Pendse, S., Thasma, S., Andhalkar, N., Avhad, G., & Kumbhar, V. (2022) · GeroScience · doi:10.1007/s11357-022-00705-1 · Cited by 173 · see citing works
“It was reported that NMN supplementation in aged mice increased NAD concentrations and improved physical activity [1], and increased treadmill running distance significantly by activating SIRT1 in skeletal muscle vascular endothelial cells [6].”
BackgroundLi, H.-R., Liu, Q., Zhu, C., Sun, X., Sun, C.-Y., Yu, C.-M., Li, P., Deng, X., & Wang, J. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102745 · Cited by 171 · see citing works
The multifaceted benefits of walking for healthy aging: from Blue Zones to molecular mechanisms
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“Endothelial protective effects of NMN have also been demonstrated in the peripheral circulation of aged mice (Das et al. 2018; Yoshino et al. 2018; de Picciotto et al. 2016), suggesting that the effects of NMN on endothelial cells in the NVU likely play a key role in NMN-induced neurovascular…”
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“We have previously reported the reduction of TAK1 expression in aging human brains (12) and aging has also been shown to lead to declined blood perfusion of tissues and organs (21).”
BackgroundEndothelial Cell Metabolism in Atherosclerosis
Theodorou, K., & Boon, R. A. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00082 · Cited by 160 · see citing works
“Interestingly, endothelial-specific overexpression of the NAD+dependent deacetylase sirtuin 1, a sensor that detects energy availability via NAD+, or supplementation of NAD precursors reverse the aging-associated decline in angiogenesis (Das et al., 2018).”
BackgroundThe role of NAD+ metabolism and its modulation of mitochondria in aging and disease
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“Another effect of aging is capillary loss, accompanied by a decline in SIRT1 activity and NAD + levels; administering the precursor NMN to aged mice in combination with exercise training restored the ability to generate new blood vessels 256 .”
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Self-citationThe role of the microcirculation in muscle function and plasticity
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Exposome and unhealthy aging: environmental drivers from air pollution to occupational exposures
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The Safety and Antiaging Effects of Nicotinamide Mononucleotide in Human Clinical Trials: an Update
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The road ahead for health and lifespan interventions
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“Improvement in endothelial blood flow and physical endurance in old mice on NMN is the result of SIRT1-dependent increase in both capillary density and hydrogen sulfide production (Das et al., 2018).”
BackgroundKiss, T., Giles, C. B., Tarantini, S., Yabluchanskiy, A., Balasubramanian, P., Gautam, T., Csípő, T., Nyúl‐Tóth, Á., Lipécz, Á., Szabó, C., et al. (2019) · GeroScience · doi:10.1007/s11357-019-00095-x · Cited by 111 · see citing works
Nicotinamide Deficiency in Primary Open-Angle Glaucoma
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Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence
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“Notably, intracellular NAD + level declines with senescence and aging 5,6 , while restoration of NAD + homeostasis reverses vascular senescence 7 and aging 8 – 10 .”
Caloric Restriction Mimetics in Nutrition and Clinical Trials
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NAD+ rescues aging-induced blood-brain barrier damage via the CX43-PARP1 axis
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Brain energy metabolism: A roadmap for future research
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SIRT1 Antagonizes Oxidative Stress in Diabetic Vascular Complication
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“H2S is also able to activate SIRT1 indirectly by increasing intracellular NAD levels (97).”
BackgroundLiao, B., Zhao, Y., Wang, D., Zhang, X., Xuan-ming, H., & Hu, M. (2021) · Journal of the International Society of Sports Nutrition · doi:10.1186/s12970-021-00442-4 · Cited by 96 · see citing works
“Regular exercise improves aerobic capacity, cardiovascular health, metabolic health, and physical function [15, 16], but many of such improvements may be NAD/sirtuins-related [17, 18].”
BackgroundInfluentialEmerging Chemical Biology of Protein Persulfidation
Vignane, T., & Filipović, M. R. (2023) · Antioxidants and Redox Signaling · doi:10.1089/ars.2023.0352 · Cited by 96 · see citing works
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Role of endothelial NAD+deficiency in age-related vascular dysfunction
Csiszár, A., Tarantini, S., Yabluchanskiy, A., Balasubramanian, P., Kiss, T., Farkas, E., Baur, J. A., & Ungvari, Z. I. (2019) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00039.2019 · Cited by 93 · see citing works
“277 Anti-aging effects of treatment with NAD boosters 278 Cellular NAD levels can be increased by up-regulating the enzymes involved in NAD 279 biosynthesis, by inhibition of NAD consumers(76), or by treatment with NAD precursors(26), 280 including niacin, nicotinamide mononucleotide (NMN)(48, 107, 159), nicotinamide…”
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Macroautophagy and aging: The impact of cellular recycling on health and longevity
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The systemic role of SIRT1 in exercise mediated adaptation
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Sirtuin 2 deficiency aggravates ageing-induced vascular remodelling in humans and mice
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Apoptosis releases hydrogen sulfide to inhibit Th17 cell differentiation
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Antiaging effects of bioactive molecules isolated from plants and fungi
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“Another study show that NMN increases physical endurance in old mice by activating SIRT1 in endothelial cells.(277) The effects of NMN are associated with increased muscle angiogenesis.”
BackgroundUrolithin A augments angiogenic pathways in skeletal muscle by bolstering NAD+ and SIRT1
Ghosh, N., Das, A., Biswas, N., Gnyawali, S. C., Singh, K., Gorain, M., Polcyn, C., Khanna, S., Roy, S., & Sen, C. K. (2020) · Scientific Reports · doi:10.1038/s41598-020-76564-7 · Cited by 78 · see citing works
Self-citationNRH salvage and conversion to NAD+ requires NRH kinase activity by adenosine kinase
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Targeting senescent cells to attenuate cardiovascular disease progression
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“EC premature senescence due to sirtuin deacetylase 1 (Sirt1) inhibition (Ota et al., 2007; Zu et al., 2010) may reversibly lead to vascular ageing and age-related decrease in exercise endurance (Das et al., 2018).”
BackgroundThe Role of Protein Persulfidation in Brain Aging and Neurodegeneration
Petrovic, D., Kouroussis, E., Vignane, T., & Filipović, M. R. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.674135 · Cited by 74 · see citing works
“The senescence of HUVEC cells (induced by oxidative stress or SIRT1 inhibition) was delayed upon H2S treatment by activating the SIRT1 protein (Das et al., 2018; Longchamp et al., 2018).”
BackgroundNAD+ Homeostasis and NAD+-Consuming Enzymes: Implications for Vascular Health
Campagna, R., & Vignini, A. (2023) · Antioxidants · doi:10.3390/antiox12020376 · Cited by 74 · see citing works
“Interestingly, in vivo NMN administration to mice, alone and in combination with exogenous hydrogen sulfide, was also proved to enhance skeletal muscle blood flow by decreasing the age-associated diminution in capillary density through the activation of vascular endothelial growth factor signaling in a SIRT1-dependent…”
BackgroundKiss, T., Tarantini, S., Csípő, T., Balasubramanian, P., Nyúl‐Tóth, Á., Yabluchanskiy, A., Wren, J. D., Garman, L., Huffman, D. M., Csiszár, A., et al. (2020) · GeroScience · doi:10.1007/s11357-020-00180-6 · Cited by 73 · see citing works
Role of hydrogen sulphide in physiological and pathological angiogenesis
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DNA methylation processes in atherosclerotic plaque
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Endothelial cell metabolism in cardiovascular physiology and disease
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“At the microvascular level, substantial evidence indicates that sirtuins, which are enzymes that use NAD + as a cofactor in deacetylation reactions, are important to preserving (coronary) microvascular functions, angiogenesis and capillary homeostasis 20,28,31,32,85 .”
InfluentialBithi, N., Link, C., Henderson, Y. O., Kim, S., Yang, J., Li, L., Wang, R., Willard, B. B., & Hine, C. (2021) · Nature Communications · doi:10.1038/s41467-021-22001-w · Cited by 68 · see citing works
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“Disruption of this balance by excessive ROS can deplete NAD + levels, and compromise vasculoprotective metabolites 28 .”
Exercise protects aged mice against coronary endothelial senescence via FUNDC1-dependent mitophagy
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Vascular Aging: Assessment and Intervention
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Metabolic regulation of exercise-induced angiogenesis
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Nitric Oxide and Hydrogen Sulfide Regulation of Ischemic Vascular Growth and Remodeling
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Geroscience and pathology: a new frontier in understanding age-related diseases
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Roles of Sirtuins in Cardiovascular Diseases: Mechanisms and Therapeutics
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NAD+ in COVID-19 and viral infections
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“Several preclinical studies demonstrate that raising NAD concentrations in endothelial cells reverses vascular and endothelial dysfunction [8,31].”
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Suppression of Endothelial AGO1 Promotes Adipose Tissue Browning and Improves Metabolic Dysfunction
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- Authors
- Das, A., Huang, G. X., Bonkowski, M. S., Longchamp, A., Li, C., Schultz, M. B., Kim, L.-J., Osborne, B., Joshi, S., Lu, Y., Treviño-Villarreal, J. H., Kang, M.-J., Hung, T.-T., Lee, B., Williams, E. O., Igarashi, M., Mitchell, J. R., Wu, L. E., Turner, N., Arany, Z., Guarente, L., & Sinclair, D. A.
- Affiliations
- Harvard University (US)
- UNSW Sydney (AU)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Guarente, Leonard
- Sinclair, David A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 173
- Issue
- 1
- Pages
- 74-89.e20
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5884172
- OpenAlex
- W2791288341
- Cited by
- 496
- References
- 87
- Citations by year
- 2026: 41 · 2025: 72 · 2024: 55 · 2023: 65 · 2022: 50 · 2021: 84 · 2020: 64 · 2019: 37 · 2018: 28
- FWCI
- 36.61
- Type
- journal article
- Language
- en
- Update notices
- erratum (2019-02-07)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- Funders
- Glenn Foundation for Medical Research (RO1 AG028730, RO1 DK100263)
- Sinclair Gift Fund
- Edward Schulak (APP1093643)
- NIH/NIA (RO1 AG015339)
- NIH/NHLBI (RO1 HL094499)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- endothelial cells, NAD+, hydrogen sulfide, vascular aging, blood flow
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Aging, Animals, Humans, Hydrogen Sulfide, Mitochondria, NAD, Physical Conditioning, Animal, Signal Transduction, Mice, Knockout, Muscle, Skeletal, Neovascularization, Physiologic, RNA Interference, RNA, Small Interfering, Vascular Endothelial Growth Factor A, Endothelial Cells, Mice, Receptors, Notch, Microvessels, Sirtuin 1
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